This is a resubmission of a competing continuation application for a SSA. The major goals are to extend research on: (1) risk and protective factors involved in adult tobacco and drug use/abuse/dependence, extending into early mid-life; (2) testing models of pathways to tobacco and drug use/abuse/dependence; (3) interactive effects of risk and protective factors; and (4) consequences of tobacco and drug use on adolescent and adult functioning. To achieve this, I wilt expand prior research by: (1) including samples of inner-city youngsters and parental drug abusers; (2) comparing the etiologies of tobacco and drug use/abuse/dependence, and their relation to psychopathology; (3) studying the intra- and intergenerational transmission of drug-prone characteristics; (4) examining cultural factors associated with tobacco and drug use/abuse/dependence; (5) studying the interaction of genetic and environmental factors on drug use/abuse/dependence; and (6) examining factors related to AIDS transmission behavior and coping with AIDS. In order to achieve these goals, an integrated program of research is underway, involving five funded large-scale projects: Studies 1A and 1B: Longitudinal studies of 976 children from ages 1-10 to early mid-life and their mothers; Studies 2A and 2B: Studies of African-American and Puerto Rican inner city youth and their mothers; Study 3: A multigenerational study of 324 offspring of the original study children in Study 2A; Study 4: A study of Black and White South African adolescents, age 12-17; Study 5: A study of 500 male HIV+ and HIV- injection drug-using fathers and their children; Study P1: A study of childhood factors for drug use/abuse extending into early mid-life, and Study P2: A study of gene-environment interactions related to drug use. The major significance of this program of integrated research is that it addresses many critical issues in the field of substance use (e.g., what are the risks for tobacco and drug use throughout the developmental span of childhood to adulthood; what can protect against these risks in different populations, including those implicated in the spread of AIDS; how can one break the transmission of risk from one generation to the next; and what are the factors associated with cessation of tobacco and drug use.) The K05 will enable me to devote my time and energy to research goals such as substantive and methodological development, mentoring activities (30% time), including guidance of medical students and junior faculty, and my own career development.